DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer

Andrew Stone; Elena Zotenko; Warwick J. Locke; Darren Korbie; Ewan K. A. Millar; Ruth Pidsley; Clare Stirzaker; Peter Graham; Matt Trau; Elizabeth A. Musgrove; Robert I. Nicholson; Julia M. W. Gee; Susan J. Clark

doi:10.1038/ncomms8758

DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer

Andrew Stone, Elena Zotenko, Warwick J. Locke, Darren Korbie, Ewan K. A. Millar, Ruth Pidsley, Clare Stirzaker, Peter Graham, Matt Trau, Elizabeth A. Musgrove, Robert I. Nicholson, Julia M. W. Gee, Susan J. Clark

Research output: Contribution to journal › Article › peer-review

Abstract

Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.

Original language	English
Article number	7758
Number of pages	9
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8758
Publication status	Published - 2015

Keywords

DNA
breast
cancer
estrogen
methylation
receptors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms8758

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@article{4d4222a19e86413e8cde6e9a8cde1a9a,

title = "DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer",

abstract = "Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.",

keywords = "DNA, breast, cancer, estrogen, methylation, receptors",

author = "Andrew Stone and Elena Zotenko and Locke, {Warwick J.} and Darren Korbie and Millar, {Ewan K. A.} and Ruth Pidsley and Clare Stirzaker and Peter Graham and Matt Trau and Musgrove, {Elizabeth A.} and Nicholson, {Robert I.} and Gee, {Julia M. W.} and Clark, {Susan J.}",

year = "2015",

doi = "10.1038/ncomms8758",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer

AU - Stone, Andrew

AU - Zotenko, Elena

AU - Locke, Warwick J.

AU - Korbie, Darren

AU - Millar, Ewan K. A.

AU - Pidsley, Ruth

AU - Stirzaker, Clare

AU - Graham, Peter

AU - Trau, Matt

AU - Musgrove, Elizabeth A.

AU - Nicholson, Robert I.

AU - Gee, Julia M. W.

AU - Clark, Susan J.

PY - 2015

Y1 - 2015

N2 - Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.

AB - Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.

KW - DNA

KW - breast

KW - cancer

KW - estrogen

KW - methylation

KW - receptors

UR - http://handle.uws.edu.au:8081/1959.7/uws:31099

U2 - 10.1038/ncomms8758

DO - 10.1038/ncomms8758

M3 - Article

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7758

ER -

DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer

Abstract

Keywords

UN SDGs

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